What if in a few decades, this same technique is used for good? Or has it already happened? I’m guessing that the yeast used in bread and wine making as well as some probiotics was developed using this method, although it may be accidental

Serial passage done by “infecting” a batch of dough or some grape juice works just the same as with animals

The current debate over whether to publish his findings, as detailed by Martin Enserink in this week’s Science, overlooks the more important issue of what could be done to treat people who might be infected with this new laboratory-generated H5N1 virus, the current circulating (and thus far poorly transmissible) H5N1 virus or an ordinary seasonal influenza virus. This is a critically important question because, as was demonstrated in the recent H1N1 pandemic, influenza scientists, vaccine companies and public health officials lacked the capacity to rapidly produce and distribute affordable supplies of pandemic vaccines and antiviral agents in time to affect the course of pandemic disease for more than 90% of the world’s people. Simply put, a global public health strategy that targeted the H1N1 virus, although scientifically sound, could not be implemented in the real world.

Fortunately, a growing body of evidence suggests it should be possible to modify the dysregulated host response (largely innate immunity) and improve survival in patients with severe influenza by treating them with immunomodulatory agents (see Influenza Other Respi Virus 2009; 3: 129-42). Cardiovascular physicians and endocrinologists already use statins, fibrates, glitazones and metformin to treat the dysregulated host responses seen patients with chronic heart diseases and diabetes. The clinical benefits and safety of these agents have been accepted for many years. A small number of studies have shown that glitazones, fibrates and metformin (but not statins) improve survival in influenza-infected mice, and do so without increasing virus replication. Observational studies show that outpatient statins reduce hospital admissions for pneumonia and inpatient statins reduce hospital mortality for laboratory-diagnosed influenza. Moreover, all of the immunomodulatory agents mentioned above are now produced as inexpensive generics in developing countries and are available to anyone who has access to basic health care. If these agents could be convincingly shown to reduce mortality in patients with severe influenza, short-term treatment of an individual patient would cost less than one dollar.

A clue to the promise of treating the host response to influenza comes from a consideration of the disparity in the case fatality rates of children and young adults seen in the 1918 and subsequent influenza pandemics (and in acute lung injury due to many other infectious and non-infectious causes; see Influenza Other Respi Virus 2009; 3: 129-42). The 1918 pandemic is notorious because it caused exceptional mortality in young adults. Many scientists have ascribed this to secondary bacterial pneumonia, but this explanation is unsatisfactory because it ignores an overwhelmingly important observation: children were infected more frequently with the virus that killed young adults and their nasopharyngeal passages were colonized more frequently with the same bacteria found in the lungs of young adults who died, yet case fatality rates in children were far lower. Why was this so? Influenza scientists have sought to explain why young adults died by studying the 1918 and other influenza viruses. Yet, despite the extraordinary contributions of influenza scientists to our understanding of the virus itself, they still cannot explain why young adults died. The question they should have been asking of the 1918 pandemic is different; they should have been asking, “why did children live?”

The dramatic switch in the mortality experiences of children and young adults in 1918 seems to have occurred at the time of puberty/menarche, and it can only be explained by fundamental differences in their host responses to influenza virus infection. This difference might reflect changes in energy metabolism: in childhood, energy metabolism is focused on growth; after puberty and menarche, it is focused on reproduction. The innate immune system has evolved to allow maximal growth in children in order to ensure their survival until the time when reproduction becomes possible. During this period, inflammatory responses take second place to growth. For those individuals who manage to survive (and for most species, only a few survive), the priority for energy metabolism becomes reproduction, and the innate immune system changes to reflect this new imperative. Now it must generate a vigorous inflammatory response to defend against attack from the outside, but it must also allow for a certain degree of immunosuppression to ensure that the fetus (foreign tissue) is not rejected. This aggressive/immunosuppressive innate immune response of reproduction-capable adults acts to ensure the continuation of the species. If on occasion it kills a few individuals, in evolutionary terms this is a small price to pay to guarantee species survival.

Theodosius Dobzhansky once wrote, “nothing in biology makes sense except in the light of evolution,” and several scientists have begun to explore the connections between energy, evolution and human disease (see Am J Clin Nutr 2011; 93(suppl): 875S-883S). Nonetheless, although studies of innate immunity have finally merited the award of the Nobel Prize, immunologists surprisingly seem to have left unexplored the different characteristics of innate immunity before and after puberty. This is more than unfortunate because, although it would be enlightening to be able to explain these differences, we already have an indication we could actually do something about them. In a unique experiment, “children” and “young adult” mice were subjected to ischemia reperfusion injury of the liver. In young adults more so than in children, this condition is highly inflammatory and often fatal. Yet glitazone treatment was able to “roll back” the often harmful host response of young adults to the more benign response of children, and this improved survival (see Influenza Other Respi Virus 2009; 3: 129-42). This singular experiment and its implications for patient care have been widely ignored.

Despite compelling scientific arguments for undertaking the laboratory and clinical research needed to show definitively that these agents would work in severe acute infections such as influenza, scientists, their paymasters and public health officials (including those at WHO and the Gates Foundation) are still focused on attacking the virus. They seem not to realize that success with host-directed treatment for influenza might be extended to the management of other diseases in which the loss of homeostatic defense mechanisms determines outcome; for example, pneumococcal sepsis, cerebral malaria, dengue hemorrhagic fever and critical illness associated with trauma and burn injury. These agents might even mitigate the pathological effects caused by pathogens considered possible agents of bioterrorism, something that $19 billion in public funding by the US government over the past decade has failed to achieve.

Almost half a century ago, physicians and public health officials learned that syndromic treatment of severe acute diarrheal illness could be accomplished with an inexpensive oral rehydration solution. Although vaccines that target a few of the pathogens responsible for these diseases have been developed since then (e.g., cholera, rotavirus), it is syndromic treatment of acute diarrheal disease with ORS that has saved millions of lives. Had decisions been made to ignore the possibility of simple and inexpensive treatment and focus solely on vaccine development, these millions would have died.

We have to ask why we have not learned from this history. Why have we not recognized that the dysregulated host response of people with acute lung injury that is seen in severe influenza and in many other conditions might be treatable with safe, inexpensive and widely available immunomodulatory agents? It takes little imagination to recognize that such treatment could be of immense importance to global public health. Yet it is remarkable that influenza scientists (and those who support their work) have been reluctant (or refused) to undertake practical experiments that seek ways to modify the host response to severe infection. Instead of explaining every last nuance of virus behaviour, they could instead try to find simple ways that physicians could use to manage their patients. By continuing to ignore the broader insights of 21st Century cell and molecular biology, they have left public health officials no alternative other than to recommend confronting global pandemic threats with hand washing and social distancing. These “technologies” represent the best of 19th Century public health practice. In the 21st Century, we can and should do much better.